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The Role of Autophagy and Related MicroRNAs in Inflammatory Bowel Disease.

1. Introduction

Inflammatory bowel disease (IBD) is divided into Crohn's disease (CD) and ulcerative colitis (UC). As a chronic nonspecific disease, the recurrent and persistent features of IBD are difficult to comprehensively cure, and the disease has a serious impact on patient quality of life. With the acceleration of urbanization and modernization, the incidence of IBD has increased to more than 0.5% of the total population of developed countries, such as in Europe and the United States [1]. The prevalence of IBD has also risen significantly in Asia, with rates in East Asia more than doubling in the past few decades [2]. IBD is generally accepted to be caused by interactions among immune deficiencies, genetic factors, and environmental factors in susceptible populations, though the specific pathogenesis remains unclear [3]. Based on recent molecular studies, researchers are recognizing that genetic factors involved in the inflammatory response and immune function and related pathways (including microRNAs and autophagy) play important roles in the pathophysiology of IBD [4].

MicroRNAs (miRNAs) are evolutionarily conserved, endogenous, single-stranded, noncoding RNAs that bind to the 3; untranslated region (UTR) and 5 UTR or partially translated region of a target mRNA [5], inhibiting transcription of the mRNA by blocking its translation [6]. Wu et al. [7] first evaluated abnormal expression of miRNAs in the intestinal tissue of UC patients in 2008, finding a specific miRNA expression pattern: three miRNAs (miR192, miR375, and miR422b) were markedly downregulated and eight (miR16, miR21, miR23a, miR24, miR29a, miR126, miR195, and let7f) notably upregulated in active UC tissues [8]. Since then, further studies have confirmed that miRNAs participate in the occurrence and development of IBD (including inactive UC) through the immune system, related inflammatory pathways, and other pathways. In addition to being related to colon cancer and inflammatory-associated cell senescence, miR-21 expression is significantly increased in intestinal fibroblasts and may participate in the IBD process through NOS2 and CD68 [9].

Autophagy is a eukaryotic cellular response to starvation, hypoxia, toxicity, other external pressures, or other stimuli. The process involves the formation of a membrane surrounding internal structures, such as organelles and cytoplasmic macromolecules, phagocytosis of intracellular components, and their presentation to the lysosome for degradation and recycling. Although the main function of autophagy is to maintain cellular homeostasis [10,11], it also plays an important role in host defense, especially in regulating inflammation [12, 13]. Autophagy defects can lead to a series of problems, including intestinal epithelial dysfunction, innate immune dysfunction, and intracellular pathogen clearance. For example, when autophagy is defective, adherentinvasive Escherichia coli (AIEC) is not addressed by the cell, and proinflammatory cytokine secretion (such as TNF-[alpha] and IL-6) increases in the intestinal tract [14, 15].

There is also recent evidence showing that miRNAs regulate autophagy via different molecular pathways and have key roles in IBD [16-20]. miRNAs can regulate intestinal autophagy by targeting IBD-relevant autophagy genes such as NOD2, aTg16L1, and IRGM, thus modulating innate intestinal immunity and intestinal epithelial function. These miRNAs are also involved in autophagy by regulating the unfolded protein response (UPR) during endoplasmic reticulum stress, which contributes to IBD intestinal fibrosis. Studies of cellular pathways have found that miRNAs can induce or inhibit intestinal autophagy by regulating NF-[kappa]B and mTOR signaling, thereby affecting inflammatory factors and anti-inflammatory or proinflammatory effects (Table 1 and Figure 1).

Several review articles to date have discussed the role of miRNAs in IBD [8, 16, 18, 19, 21-25], However, there are no reviews that focus on the IBD field and on miRNAs that regulate autophagy and associated pathways. Elucidation of the interaction between miRNAs and autophagy in IBD-specific mechanisms will help to explain the occurrence, development, and future molecular targets of IBD therapy. This article aims at summarizing the mechanism of miRNAs related to IBD that regulate autophagy via different pathways and to provide a theoretical reference for further research.

2. IBD-Relevant Autophagy Genes

Widely accepted IBD-relevant autophagy genes, including NOD2, ATG16L1, and IRGM, were identified through genome-wide association studies (GWASs) and subsequent meta-analyses of GWAS and immune chip data [26]. These studies have been crucial to elucidating the mechanisms underlying IBD, particularly autophagy and innate immunity in CD and intestinal epithelial barrier dysfunction in UC. They have also provided clues for novel IBD therapeutic strategies [18].

2.1. NOD2. NOD2 is the first gene thought to predict increased susceptibility to CD. The NOD2 protein is a cytoplasmic receptor that senses bacterial wall peptides and promotes clearance by initiating proinflammatory transcription [27]. Because NOD2 signaling can activate autophagy, it has recently been shown that the NOD2 pathway and autophagy are cross-regulated, and this relationship plays a positive role in intracellular bacterial clearance [28, 29].

It has also been reported that miR-142-3p effectively inhibits autophagy in a NOD2-dependent manner and downregulates IL-8 mRNA expression [30]. There is a negative correlation between NOD2 and miR-320 expression: miR-320 downregulates NOD2 mRNA and protein expression. In IBD, expression of miR-320 in intestinal mucosa is significantly decreased, which may explain the observed rise in NOD2 expression [31,32]. Researchers have also identified the interaction between miR-192 and NOD2 as possibly being related to the pathogenesis of IBD. miR-192, the most highly expressed UC-associated miRNA, appears to be dysfunctional in the intestinal epithelial cells of patients with IBD. Additionally, miR-192 significantly alters expression of NOD2 mRNA and protein and significantly reduces phosphorylation of NF-[kappa]B and expression of IL-8 and CXCL3 [17, 33].

As NF-[kappa]B has an inhibitory effect on autophagy (see Section 3.1) [34], it may have a key function in the pathogenesis of IBD and the innate immune response of intestinal epithelial cells [33]. miR-122 regulates the PI3K/Akt/mTOR/ p70S6K pathway in breast cancer and downregulates NOD2 expression [35]. In CD, miR-122 targets NOD2 and reduces lipopolysaccharide- (LPS-) induced apoptosis by inhibiting NOD2, a process that activates the NF-[kappa]B pathway. Because activation of NF-[kappa]B has an inhibitory effect on autophagy, miR-122 can play an autophagy-related role in IBD [36]. In addition, by regulating NOD2 and proinflammatory cytokines, miR-146a may be important in IBD; however, it still needs to be verified whether miR-146a affects autophagy via NOD2 [37].

2.2. ATG16L1. ATG16L1 is an important adapter protein in the autophagosome formation that occurs during autophagy [38]. Some human and animal studies have shown that ATG16L1 dysfunction is closely related to intestinal inflammation in CD [16, 39]. miR-142-3p was recently shown to negatively regulate ATG16L1 in CD colon epithelial cells. Upregulation of miR-142-3p decreases expression of ATG16L1 mRNA and protein, thereby reducing the autophagic activity of related cells [30, 40]. AIEC infection can lead to overexpression of miR-93 and miR-106B, inhibition of ATG16L1, and downregulation of ATG5, causing a reduction in autophagosome formation and thus interfering with the autophagy pathway and bacterial clearance [41]. In intestinal epithelial HCT116 cells, miR-106b targets ATG16L1 and modulates autophagy, partially through a binding site at the 3' end of the ATG16L1 3 UTR. In addition, miR-106aregulated autophagy may also occur in an ATG16L1-independent manner [42]. In ovarian cancer cells, NF-[kappa]B transcriptionally upregulates miR-130a expression in response to inflammatory stimuli, and miR-130a can increase levels of p-mTOR and impair LC3-II accumulation, leading to blockade of rapamycin- or starvation-induced autophagy [43]. AIEC also enhances expression of miR-30C and miR130a by activating NF-[kappa]B, resulting in the downregulation of ATG5 and ATG16L1 and inhibition of autophagy. This study also revealed that the signaling pathway through which this occurs may be effective in inducing the proinflammatory cytokine IL-8, leading to defects in autophagy-mediated clearance of AIEC [44].

Vitamin D receptor (VDR) activation downregulates expression of ATG16L1 and its related lysozyme, impairing the antibacterial effect of Paneth cells and resulting in defective autophagic function in intestinal inflammatory cells [45]. VDR is the target of miR-346, and TNF-[alpha] induces miR-346 expression during intestinal mucosal inflammation, which downregulates VDR in the intestinal epithelium and affects autophagy [46]. Gene set enrichment analysis (GSEA) has demonstrated that miR-20a expression is negatively correlated with the autophagy-lysosome pathway. Indeed, miR20a regulates several genes related to autophagy and inhibits ATG16L1, BECN1, and SQSTM1 protein expression [47]. One study found miR-20a to be significantly increased in the intestinal mucosa of pediatric CD patients [48].

2.3. IRGM. Immunity-related GTPase family M protein (IRGM) has been considered to be associated to autophagy since 2006, though its specific molecular association with autophagy remains unclear [49]. More recent studies have shown that IRGM proteins play important roles in innate immunity against intracellular pathogens (such as CD-associated AIECs) [15, 50]. IRGM-dependent autophagy plays an important role in combating pathogenic AIEC, and the abundance of pathogenic AIEC has been demonstrated to be higher in the intestinal mucosa of CD patients than in that of healthy controls [51]. Furthermore, studies have shown that IRGM regulates autophagy by affecting mitochondrial division [52]. By regulating IRGM expression, miR-196 may participate in the endogenous fine-tuning of autophagic pathway initiation and in the control of intracellular pathogen degradation in human cells. miR-196 has also been shown to be overexpressed in inflammatory intestinal epithelial cells in CD. This expression downregulates the IRGM protective variant (c.313C) but not the risk-associated allele (c.313T), suggesting that CD-associated risk (T allele) and protective (C allele) haplotypes confer differences in IRGM expression under the control of miR-196. Notably, this regulatory mechanism does not appear to occur in all cell types. Additionally, overexpression of miR-196 can also induce downregulation ofLC3II transformation, inhibiting LC3II accumulation. In other words, miR-196 inhibits autophagy from its initiation step. Downregulation or loss of IRGM expression may also impair the control of autophagy (xenophagy) of CD-associated AIEC in cellular replication [53].

3. Endoplasmic Reticulum Stress Pathway

3.1. Effect of Endoplasmic Reticulum Stress on Autophagy in IBD. GWASs have identified endoplasmic reticulum (ER) stress as being associated with IBD because such stress is increased in inflammatory intestinal epithelial cells [54]. ER stress is a cellular process that is triggered by the folding of multiple interfering proteins in the endoplasmic reticulum. This process allows cells to cope with an excess of misfolded or expanded proteins through a complex signaling network known as the UPR [55], which can rebalance the ER through an adaptive mechanism involving autophagy. Defects in autophagy invoke the ER stress response [56], promoting autophagy [57]. XBP1 and ORMDL3 are two genes involved in UPR that are thought to be associated with IBD, and lack of their expression can promote intestinal inflammation [58, 59]. Deletion of XBP1 enhances activation of IRE1 and sensitizes intestinal epithelial cells to inflammatory cytokines [59]. Directly upstream of XBP1, IRE1 is a kinase that can induce activation of JNK signals under ER stress through interaction with TRAF2 [60]. JNK directly induces formation of autophagosomes by LC3 (Figure 2) [61]. ORMDL3 regulates [Ca.sup.2+] uptake in the ER, and ORMDL3 dysfunction results in protein misfolding and increased sensitivity to ER stress. The underlying mechanism of these molecular interactions with regard to intestinal inflammation remains unclear [62, 63].

3.2. Regulation ofmiRNAs via the ER Stress Pathway. Studies have shown that miRNAs can regulate ER stress and induce autophagy [64]. miR-665 has been shown to be upregulated in the intestinal mucosa of patients with IBD and can downregulate expression of XBP1 and ORMDL3 during ER stress, increasing JNK activity and leading to an increase in inflammatory factor-induced apoptosis and autophagy sensitivity. Additionally, miR-665 may be important in the positive feedback regulation of the miR-665/ER/NF-[kappa]B loop, resulting in chronic inflammation of the gastrointestinal tract, but the mechanism requires further validation [65]. Expression of miR-375, which regulates ER stress, is elevated in normal colon tissue and significantly reduced in intestinal inflammation [66, 67]. However, because its specific mechanism is not clear, involvement of miR-375 in regulating autophagy in IBD through ER stress modulation requires further study. In HeLa cells, miR-346 was found to be induced under ER stress and to modulate autophagic flux. GSK3B has been shown to be the target of miR-346 and to participate in ER stress-related autophagy. miR-346 activates autophagy by interrupting the association between BCL2 and BECN1 in a GSK3B-dependent manner. However, whether this mechanism plays a role in IBD remains to be studied [68].

Additionally, miR-150 may regulate fibroblast autophagy via ER stress and function in IBD intestinal fibrosis. Studies have shown that IRE1a has a splicing effect on XBP1. The IRE1[alpha]-XBP1 axis leads to the expansion of the ER, enhancing its ability to secrete extracellular matrix proteins and activate myofibroblasts. An increase in [alpha]SMA expression is a characteristic of fibroblast transformation into myofibroblasts. miR-150 inhibits expression of the transcription factor c-Myb (the primary target of miR-150, which can increase expression of [alpha]SMA), thereby reducing expression of [alpha]SMA to exert an antifibrosis effect. Although IRE1a can directly regulate degradation of miR-150, the loss of IRE1[alpha] activity may lead to an increase in miR-150 levels [69]. Because the absence of XBP1 enhances activation of IRE1 during endoplasmic reticulum stress [59], expression of miR-150 is speculated to be reduced, and any antifibrosis effect is expected to be weakened. miR-150 is expressed in the serum of IBD (UC) tissues [4] and may thus regulate fibroblast autophagy via ER stress and play a role in IBD intestinal fibrosis (Figure 2).

IRE1 interacts with TRAF2 to activate JNK signaling, and JNK directly induces formation of autophagosomes via LC3, leading to enhanced autophagy. The IRE1[alpha]-XBP1 axis leads to the expansion of the endoplasmic reticulum, enhancing its ability to secrete extracellular matrix proteins and activate myofibroblasts. XBP1 deficiency in endoplasmic reticulum stress leads to enhanced IRE1 activation, decreased miR-150 expression, and reduced c-Myb inhibition, leading to greater expression of aSMA, expansion of the endoplasmic reticulum, enhancement of extracellular matrix protein secretion capacity, and activation of fibroblast transformation into myofibroblasts, ultimately leading to fibrosis.

4. Signaling Pathway

4.1. NF-[kappa]B, MAPK (JNK), and FOXO3a. NF-[kappa]B activates a variety of signaling molecules, including Toll-like receptors and cytokine receptors, which play an important role in inflammation, immune responses, cell proliferation, cell differentiation, and apoptosis [70]. Autophagy inhibits NF-[kappa]B activation, and NF-[kappa]B suppresses autophagy [34]. Autophagy attenuates NF-[kappa]B in inflammation, whereas inhibition of autophagy activates NF-[kappa]B by blocking the formation of autophagosomes and promoting autophagosome accumulation. Activation of NF-[kappa]B also induces the upregulation of p62 and JNK to form a positive feedback loop that inhibits autophagy [71, 72]. c-Jun N-terminal protein kinase (JNK) is a serine/threonine kinase and mitogen-activated protein kinase (MAPK) in mammals that is a core component of the autophagic signaling pathway. Phosphorylated JNK promotes autophagy through upstream Bcl2 family protein kinases [73]. FoxO3a enhances autophagy in response to environmental stress and activates autophagy by binding directly to the promoters of autophagy-related genes such as LC3, Beclin1, and Atg12. FoxO3a can also be phosphorylated and inactivated by PI3K/Akt. Akt phosphorylation reduces FoxO3a transcriptional activation by inhibiting FoxO3a translocation to the nucleus. Autophagy might be induced by the Akt/FoxO3a pathway to protect cells in the early stage of environmental stress. Autophagy is decreased in the later stage, but FoxO3a expression continues to increase, subsequently upregulating p-Akt expression [74]. Additionally, mTOR enhances the NF-[kappa]B signaling pathway by downregulating expression of FOXO3, suggesting an ability to inhibit autophagy [75].

Studies have shown that miR-146b overexpression activates and upregulates the NF-[kappa]B pathway, thereby inhibiting autophagy, improving intestinal epithelial function, reducing intestinal inflammation in dextran sulfate sodium- (DSS-) induced colitis mice, and increasing the survival rate of fatal colitis [76]. Substance P (SP) also increases NF-[kappa]B pathway activation in colonic epithelial cells [77, 78] by regulating expression of miR-221-5p via the MAPK and NF-[kappa]B pathways, and miR-221-5p negatively regulates expression of proinflammatory cytokines in colonic epithelial cells by responding to SP. The increased expression of miR-221-5p in human and mouse colitis tissues, which elevates SP expression, suggests a role in IBD autophagy [79]. Moreover, because they are upregulated in IBD patients and in mouse inflammatory bowel tissues, miR-132 and miR-223 have been reported to be important mediators in IBD pathogenesis. They can inhibit expression of IKBa by negatively regulating FOXO3a, leading to the enhancement of NF-[kappa]B signaling and increasing the production of proinflammatory cytokines [80]. In another study [81], JNK signaling was shown to be upstream of miR-223, and activation of JNK induced miR223 expression. Therefore, we speculate that JNK signaling is activated in IBD and that it upregulates miR-223 expression, leading to the enhancement of NF-[kappa]B signaling and downregulation of FOXO3a. This process plays a role in inhibiting autophagy. In addition, miR-21 is overexpressed in intestinal inflammation and tissue injury, which can suppress autophagy (see Section 3.2). Upregulation of miR-21 has been found in ovarian cancer cells in association with activation of the JNK-1/c-Jun pathway [82]. Nonetheless, it remains unclear whether these mechanisms regulate (inhibit) autophagy in IBD.

4.2. mTOR, Akt, PI3K, and PTEN. Mammalian target of rapamycin (mTOR) is a serine/threonine kinase. Inhibition of mTORC1-induced autophagy using genetic or pharmacological methods was first achieved in yeast studies [83]. In mammals, mTORC1 inhibits autophagy initiation through phosphorylation [84, 85]. Akt is an intracellular serine/threonine kinase that is downstream of phosphatidylinositol-3 kinase (PI3K). Phosphorylated Akt (p-Akt) activates mTOR, as reflected by an increase in p-mTOR expression, leading to autophagy inhibition [86]. Related studies have shown that miR-155 can increase Akt activation by decreasing expression of SHIP-1, resulting in enhanced mTORC1 expression, and inhibition of miR-155 can reduce the inflammatory reaction in experimental colitis. The PI3K-AKT signaling pathway was strongly activated by sustained overexpression of miR-155 in DHL16 cells [75, 87-89]. However, whether miR-155 plays a role in autophagy in IBD remains to be studied. Knockdown of mouse miR-21 reduces the effect of inflammation on tissue damage and increases survival rates in DSS-induced lethal colitis [90]. miR-21 has also been shown to specifically inhibit autophagy in a variety of diseases. For example, overexpression of Rab11a increases expression of LC3II and beclin-1 in renal ischemia. miR-21 directly inhibits Rab11a expression, thereby inhibiting autophagy, and participates in the Akt/PTEN pathway to inhibit autophagy in primary liver cancer [90-94]. In contrast, some studies have shown that miR-21 inhibits p-Akt and deactivates mTOR to induce autophagy [95, 96]. PTEN, a potential target gene of miR-21, acts as a lipid phosphatase that antagonizes PI3K signaling. miR-21 inhibition increases PTEN protein levels and suppresses AKT phosphorylation [95, 97]. More research is needed to determine whether miR-21 inhibits or induces autophagy in IBD via these pathways. One study has also demonstrated that miR-106b and miR-93 regulate cell progression by suppressing PTEN and enhancing activity of the PI3K/Akt pathway. Regardless, it remains to be verified whether these miRNAs play the same role in IBD [98].

5. Conclusion

The important role of miRNA in IBD pathophysiology has been clarified in recent years with increasing molecular evidence on IBD occurrence and development. Current studies on miRNA-related mechanisms in IBD mainly focus on three components: immune homeostasis disorder, intestinal epithelial barrier dysregulation, and autophagy regulation [16]. However, few studies have attempted to identify which miRNA may be more linked to autophagy in IBD, and the functions of miRNAs in the autophagy pathway in IBD have only been addressed with cellular experiments but few in vivo experiments. In addition, the mechanisms of the NOD2 and NF-[kappa]B pathways appear to have garnered the most attention. It is likely that other signal pathways will be linked to IBD, including the classic autophagy pathway LKB1/AMPKPI3K/AKT and beclin-1/bcl-2. Therefore, more studies must be performed in the future to expand these fields. Additionally, although many studies have demonstrated that miRNAs regulate related proteins in the autophagy pathway, only a few studies have investigated the effect of miRNA on autophagy flux. As autophagy is a dynamic biological process, it would be interesting to elucidate the role of miRNAs in autophagic flux.

Study of the molecular expression mechanisms of miRNAs in IBD may lead to IBD molecular targeted therapy. Given the function of miRNAs in regulating autophagy in IBD pathogenesis, exploring the potential of miRNAautophagy-based therapeutics is also needed. As it has been identified as a new diagnostic/prognostic tool, miR-21 may serve as a therapeutic target in the future. Nonetheless, before application of this basic research to the clinic can occur, many technical issues need to be overcome. For example, a single miRNA can interact with multiple genes or tissues in vivo, and it may be involved in multiple signaling pathways. Using inhibitors may lead to suboptimal side effects by affecting many pathways in different type of cells. Therefore, identification of IBD-associated miRNA autophagic networks and exploration of specific miRNAs as targets for the treatment of IBD is very important. There are two completed phase I trials (NCT00688012 for a single ascending dose and NCT00979927 for multiple ascending doses; drug: SPC3649) funded by Santaris Pharma related to a locked nucleic acid- (LNA-) modified oligonucleotide that specifically inhibits endogenous miR-122, resulting in prolonged dose-dependent reductions in hepatitis C virus (HCV) RNA levels without evidence of viral resistance [25, 100].

In summary, both miRNAs and autophagy play an important role in IBD. The effect of miRNA on autophagy is a promising field of study for exploring IBD treatment. A deeper understanding of the complex dialog between miRNAs and autophagy and their exact roles in IBD may lead to a great success in the future.

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this article.

Authors' Contributions

Shiyuan Wang, Yan Huang, and Cili Zhou have the same rights; Shiyuan Wang, Yan Huang, and Cili Zhou compiled the complete draft and modification of the manuscript; Jimeng Zhao, Luyi Wu, Min Zhao, and Fang Zhang reviewed the literature; Huirong Liu and Huangan Wu conceptualized the study; and all authors approved the final version of the manuscript.


This work was supported by the National Natural Sciences Foundation of China (no. 81574079); the National Basic Research Program of China (973 program, no. 2015CB554501); the Program of Shanghai Academic Research Leader (17XD1403400); the Shanghai Leading Talent Program (2016 no. 037); the "Shuguang Program" supported by the Shanghai Education Development Foundation and the Shanghai Municipal Education Commission (14SG39).


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Shiyuan Wang (iD), (1, 2) Yan Huang (iD), (2) Cili Zhou (iD), (2) Huangan Wu (iD), (2) Jimeng Zhao (iD), (2) Luyi Wu, (1) Min Zhao (iD), (1, 2) Fang Zhang (iD), (2) and Huirong Liu (iD) (2)

(1) Key Laboratory of Acupuncture-Moxibustion and Immunology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China

(2) Shanghai Research Institute of Acupuncture and Meridian, Shanghai 200030, China

Correspondence should be addressed to Huirong Liu;

Received 31 January 2018; Revised 26 April 2018; Accepted 15 May 2018; Published 4 June 2018

Academic Editor: Amosy M'Koma

Caption: Figure 1: miRNAs regulate cell autophagy via different molecular pathways in the process of IBD.

Caption: Figure 2: Endoplasmic reticulum stress and autophagy.
Table 1: Summary of miRNAs that regulate autophagy in IBD.

MicroRNA            Samples         Diseases    Target      Effects on
                                    CD   UC                 autophagy

miR-142-3p *         HCT116         +    -     ATG16L1,      Inhibit

miR-320              HT-29          +    +       NOD2,       Inhibit

miR-192 *            HCT116         +    -       NOD2,       Inhibit

miR-122              HT-29          +    -       NOD2,       Inhibit

miR-93;           Human colon       +    -      ATG16L1      Inhibit
miR-106B        tissues, HCT116                  PTEN

miR-30C;        Human intestinal    +    -       ATG5,       Inhibit
miR-130a         epithelial T84                 ATG16L1
                   cells/mice                    mTOR

miR-346         Human intestinal    +    +     Vitamin D    Upregulate
                epithelial cells               receptor

miR-20a          Human colonic      +    -      BECN1,       Inhibit
                mucosal tissues                ATG16L1,

MiR-196 *       Human epithelial    +    -      LC3-II,      Inhibit
                     cells                       IRGM

miR-665            Human/mice       +    +       XBP1,        Induce
                colonic mucosal                 ORMDL3

miR-150        Intestinal tissue    -    +       c-Myb       Unclear

miR-146b          Mice colonic      -    +       siah2       Inhibit
                    tissues.                     FOXO3

miR-221-5p       Human colonic      +    +     Substance     Inhibit
                epithelial cells                   P

miR-132;           Human/mice       +    +      FOXO3a,      Inhibit
miR-223         colonic tissues                   JNK

miR-155 *         Mice colonic      -    +      SHIP-1,      Inhibit
                    tissues                     FOXO3a

                                                Akt, m-      Inhibit/
miR 21 **         Mice colonic      -    +     TOR, JNK,      induce
                    tissues.                     PTEN

MicroRNA                  Potential mechanism               Years and

miR-142-3p *   Decreases ATG16L1 mRNA and protein levels;   2014 [30]
                  modulates NOD2-dependent autophagy;       2018 [40]
                     inhibits IL8 mRNA expression.

miR-320              Downregulates NOD2 expression.         2016 [31]

miR-192 *      Downregulates NOD2 expression; suppresses    2014 [33]
                         NF-[kappa]B activity.

miR-122          Suppresses NOD2; increases NF-[kappa]B     2017 [35]
                               activity.                    2013 [36]

miR-93;          Targets ATG16L1 messenger RNA; reduces     2014 [41]
miR-106B         levels of ATG16L1; prevents autophagy/     2017 [98]
                 dependent eradication of intracellular
                 bacteria; suppresses PTEN by enhancing
                   activity of the PI3K/Akt pathway.

miR-30C;        Reduced levels of ATG5 and ATG16L1; miR-    2014 [44]
miR-130a        130a increases levels of p-mTOR; impairs
                          LC3-II accumulation.              2017 [43]

miR-346        Downregulates VDR, leading to upregulation   2014 [46]
                   of ATG16L1; activates autophagy by       2018 [68]
               interrupting the association between BCL2
                 and BECN1 in a GSK3B-dependent manner.

miR-20a        Downregulates BECN1, ATG16L1, and SQSTM1.    2017 [47,

MiR-196 *           Inhibits accumulation of LC3-II.        2011 [53]

miR-665          Represses XBP1 and ORMDL3 expression.      2017 [65]

miR-150        Inhibits c-Myb, leading to decreased aSMA;   2016 [69]
                     exhibits antifibrotic effects.

miR-146b        Decreases expression of siah2; activates    2013 [76]
                        the NF-[kappa]B pathway.            2016 [99]

miR-221-5p      Decreases siah2 and FOXO3 expression. SP    2014 [79]
                regulates miR-221-5p expression through
                the MAPK and NF-[kappa]B pathways; miR-
               221-5p negatively regulates expression of
                  proinflammatory cytokines in colonic
                  epithelial cells in response to SP.

miR-132;        Suppresses the level of I[kappa]B[alpha]    2016 [80]
miR-223        through downregulation of FOXO3a, leading    2015 [81]
                 to enhanced NF-[kappa]B signaling; JNK
                       signaling induces miR-223.

miR-155 *        Increases Akt activation by decreasing     2017 [87]
               SHIP-1 expression, leading to upregulation   2015 [75]
               of mTOR; downregulates FOXO3a, leading to    2012 [89]
               enhanced NF-[kappa]B signaling; activates
                         the PI3K-Akt pathway.

                Unclear-decreases phosphorylated AKT and
miR 21 **       deactivates the mTOR NK-1-c-Jun pathway;    2013 [90,
                  promotes miR-21 upregulation. miR-21         96]
                inhibition enhances PTEN protein levels
                   and inhibits AKT phosphorylation.

                Inhibits autophagy via the PTEN/Akt/mTOR    2015 [95]
                                pathway.                    2014 [82]
                                                            2018 [97]

* refers to more closely related to IBD; xx refers to the most studied
in IBD [8, 16, 25].
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Author:Wang, Shiyuan; Huang, Yan; Zhou, Cili; Wu, Huangan; Zhao, Jimeng; Wu, Luyi; Zhao, Min; Zhang, Fang;
Publication:Gastroenterology Research and Practice
Date:Jan 1, 2018
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